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Avoidance learning in rats devoid of the telencephalon plus thalamus.

Two experiments were undertaken to investigate whether learning of an inhibitory avoidance response is possible in rats devoid of the whole forebrain, except for the hypothalamus. In experiment I all telencephalic structures were surgically ablated. Twenty-four hours later the rats were given a learning trial in the up-hill avoidance task. When tested 2 h later, the animals given a tail-shock contingent on the up-hill response showed significant increases in step-up latencies in comparison with control groups that had received non-contingent shock or no shock. In experiment II the thalamus was removed in addition to the telencephalon. As in experiment I, the animals received either tail-shock contingent on the up-hill reaction, no tail-shock, or non-contingent shock. When tested 2 and 24 h after the training, the animals that had received response-contingent shock showed significant increases in latencies to ascend the platform. These results indicate that inhibitory avoidance conditioning is still possible in rats devoid of the telencephalon plus thalamus.

Animals↗

Effect of propranolol treatment in pregnant rats on motor activity and avoidance learning of the offspring.

Rats born to mothers treated with propranolol, during days 8-22 of gestation, displayed hyperactivity in the open field which lasted up to 60 days of age and an impairment of avoidance in the shuttle box which was more marked in the male rats. Females exhibited hyperactivity in the open field but developed impaired avoidance learning only when exposed prenatally to both propranolol and hypoxia. Propranolol administration during the last term of pregnancy (days 18-22) affected mostly shuttle box performance. In contrast, hyperactivity could be induced by treatment during various stages of pregnancy, (days 8-22, 8-18, or 18-22) with the duration of hyperactivity being directly related to the length of treatment of the mothers. The possible mechanism of the disruptive effect of propranolol in the fetus and newborn is discussed.

Aging↗

Differential patterns of extracellular signal-regulated kinase-1 and -2 phosphorylation in rat limbic brain regions after short-term and long-term inhibitory avoidance learning.

Activation of the extracellular signal-regulated kinase-1 and -2 has been shown to be required for neural plasticity and memory. Previous pharmacological studies have demonstrated that inhibition of extracellular signal-regulated kinase-1 and -2 blocks inhibitory avoidance retention. The aim of the present study was to investigate the different neural substrates underlying short- and long-term inhibitory avoidance learning and memory in rats using phosphorylated extracellular signal-regulated kinase-1 and -2 labeling as an index of plasticity. Short- and long-term retention tests were given 10 min or 24 h after inhibitory avoidance training. A significant elevation in the number of phosphorylated extracellular signal-regulated kinase-1 and -2-immunoreactive neurons was observed in area 1 of anterior cingulate cortex, the secondary motor cortex, lateral orbital cortex, claustrum, and the medial amygdala nucleus after the short-term inhibitory avoidance test. After the long-term retention test, phosphorylated extracellular signal-regulated kinase-1 and -2-immunoreactive neurons were localized in area 1 of anterior cingulate cortex, prelimbic cortex, and the central nucleus of amygdala. This suggests that phosphorylated extracellular signal-regulated kinase-1 and -2-immunoreactivity may reveal different brain regions involved in the storage of short- and long-term aversive memories.

Animals↗

Avoidance learning: long-lasting deficits after temporal lobe seizure.

Microinjections of carbachol (carbamylcholine chloride) into the amygdaloid complex of rats produced behavioral and electrophysiological seizures which subsided within 24 hours. A persisting functional change caused a deficit in avoidance learning 1 to 3 weeks after the seizure. A cholinergic system is implicated by the fact that cholinergic blockade (scopolamine) of the amygdala during training reversed the effects of the seizures induced by carbachol.

Amygdala↗

Strain-dependent effects of gamma-L-glutamyl-L-aspartate, a NMDA antagonist, on retention of a Y-maze avoidance learning task in mice.

The NMDA receptor antagonist, gamma-L-glutamyl-L-aspartate (gamma-LGLA), suppressed spontaneous improvement in posttraining performance in Swiss mice during the hours following acquisition of a Y-maze avoidance learning task. Since variability in posttraining performance is at least partially due to genetic factors, we compared the effects of gamma-LGLA on retention of Y-maze learning in C57BL/6J, DBA/2J and BALB/c mice. Mice had to leave the start alley of the maze within the first 5 s (temporal component) and to choose the left alley (spatial component). C57BL mice significantly improved their performance from 1 h to 24 h posttraining, whereas DBA/2J and BALB/c mice did not. However, only retention of the temporal component improved over time in C57BL. gamma-LGLA administered immediately posttraining (0.025-25 mumol/kg, i.p.) dose-dependently impaired retention of the temporal component in C57BL mice 48 h later, but had no significant effect on retention of the spatial component. gamma-LGLA administered 24 h posttraining induced a similar but weaker deficit. In contrast, gamma-LGLA did not significantly affect retention of DBA/2J and BALB/c mice, regardless of the component analyzed or the time of administration. It had no effect on locomotor activity or emotional reactivity of animals of any strain. These results support the hypothesis of a specific action of gamma-LGLA on mechanisms involved in the treatment of information during the hours following acquisition, and suggest that NMDA receptors are involved in this action.

Animals↗

Passive avoidance learning in the young chick results in time- and locus-specific elevations of alpha-tubulin immunoreactivity.

A monoclonal antibody was used to examine changes in immunoreactivity of the cytoskeletal protein, alpha-tubulin, following passive avoidance learning in day-old chicks. Postmitochondrial fractions (16,000 g supernatants) were prepared from specific forebrain loci taken at several time points after training and assayed with the anti-alpha-tubulin antibody, YL1/2. Of the regions examined, elevations in the titre of YL1/2 were found in the left intermediate hyperstriatum ventrale 1 h, 6 h and 24 h following training, in the left lobus parolfactorius 1 h following training and in the right lobus parolfactorius 6 h and 24 h following training. No training-related changes were detected in a third forebrain region, the paleostriatum augmentatum. These results regarding the cellular dynamics of memory formation in the chick confirm and expand on earlier findings from our laboratory.

Animals↗

NMDA receptor antagonists antagonize the facilitatory effects of post-training intra-basolateral amygdala NMDA and physostigmine on passive avoidance learning.

In the present study, the effects of post-training intra-basolateral amygdala (BLA) injection of an N-methyl-d-aspartate (NMDA) receptor agonist and competitive or noncompetitive antagonists, on memory retention of passive avoidance learning was measured in the presence and absence of physostigmine in rats. Intra-BLA administration of lower doses of NMDA (10(-5) and 10(-4) microg/rat) did not affect memory retention, although higher doses of the drug (10(-3), 10(-2) and 10(-1) microg/rat) increased memory retention. The greatest response was obtained with 10(-1) microg/rat of the drug. The different doses of the competitive NMDA receptor antagonist DL-AP5 (1, 3.2 and 10 microg/rat) and noncompetitive NMDA receptor antagonist MK-801 (0.5, 1 and 2 microg/rat) decreased memory retention in rats dose dependently. Both competitive and noncompetitive NMDA receptor antagonists reduced the effect of NMDA (10(-2) microg/rat). In another series of experiments, intra-BLA injection of physostigmine (2, 3 and 4 microg/rat) improved memory retention. Post-training co-administration of lower doses of NMDA (10(-5) and 10(-4) microg/rat) and physostigmine (1 microg/rat), doses which were ineffective when given alone, significantly improved the retention latency. The competitive and noncompetitive NMDA receptor antagonists, DL-AP5 and MK-801, decreased the effect of physostigmine (2 microg/rat). Atropine decreased memory retention by itself and potentiated the response to DL-AP5 and MK-801. It may be concluded that amygdalar NMDA receptor mechanisms interact with cholinergic systems in the modulation of memory.

Amygdala↗

Effects of (-)-S-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate monohydrate (YM796), a novel muscarinic agonist, on disturbance of passive avoidance learning behavior in drug-treated and senescence-accelerated mice.

Effects of YM796 (-)-S-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate monohydrate; a novel muscarinic agonist, were observed on disturbance of passive avoidance learning behavior in drug- (protein synthesis inhibitor and anticholinergic drugs) treated and senescence-accelerated mice in comparison with those of a muscarinic agonist (AF102B) and acetylcholinesterase inhibitors (E2020 (1-benzyl-4-[(5,6-dimethoxy-1-indanone-2-yl) methyl] piperidene hydrochloride), NIK247 [9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate hydrochloride], THA (9-amino-1,2,3,4-tetrahydroacridine) and physostigmine). All tested drugs administered before training significantly prolonged the shortened latency of step-through induced by the protein synthesis inhibitor cycloheximide (150 mg/kg s.c.). This shortened latency was also significantly prolonged when YM796 was administered immediately after training, but not when administered before the test trial. The ameliorating effect of YM796 on the impairment in learning behavior by cycloheximide was significantly suppressed by pirenzepine (0.1 micrograms/mouse i.c.v.). When administered before training, all test drugs prolonged the shortened latency of step-through induced by treatment with the anticholinergic drugs [scopolamine (1 mg/kg s.c.) and hemicholinium-3 (0.3 microgram/mouse i.c.v.)], suggesting that they ameliorated the impairment of learning behavior. This shortened latency in scopolamine-treated mice was also significantly prolonged by YM796, AF102B, E2020, NIK247 and physostigmine when administered immediately after training, but not when administered before the test trial. The pharmacological actions of YM796 administered immediately after training and before the test trial in hemicholinium-3-treated mice were similar to those in scopolamine-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

Deficits in passive avoidance learning in young rats following mecamylamine injections in the hippocampo-entorhinal area.

Young rats 11, 13, 16, and 20 days old were injected bilaterally with the nicotinic antagonist mecamylamine hydrochloride (5, 50, and 100 micrograms on each side) into the posteroventral hippocampo-entorhinal (VHE) area and trained on a "cool-draft-stimulus" passive avoidance task. The data showed impaired acquisition and reduced resistance to extinction. The deficits observed were age- and dose-dependent, rats being highly sensitive to the drug when 11 and 13 days old and decreasingly responsive up to day 20. The results may indicate that nicotinic cholinergic sites in the VHE area mediate passive avoidance learning in the young rat as soon as acquisition emerges. Muscarinic cholinergic mechanisms only develop later in this region, becoming progressively more important for passive avoidance behavior.

Animals↗

NMDA receptor antagonism in the basolateral amygdala blocks enhancement of inhibitory avoidance learning in previously trained rats.

Extensive evidence suggests that N-methyl-D-aspartate (NMDA) glutamate receptor channels in the amygdala are involved in fear-motivated learning, and infusion of NMDA receptor antagonists into the amygdala blocks memory of fear-motivated tasks. Recent studies have shown that previous training can prevent the amnestic effects of NMDA receptor antagonists on spatial learning. In the present study, we evaluated whether infusion of the NMDA antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) into the basolateral nucleus of the amygdala (BLA) impairs reinforcement of inhibitory avoidance learning in rats given previous training. Adult male Wistar rats (220-310 g) were bilaterally implanted under thionembutal anesthesia (30 mg/kg, i.p.) with 9.0-mm guide cannulae aimed 1.0 mm above the BLA. Infusion of AP5 (5.0 microg) 10 min prior to training in a step-down inhibitory avoidance task (0.4 mA footshock) blocked retention measured 24 h after training. When infused 10 min prior to a second training session in animals given previous training (0.2 mA footshock), AP5 blocked the enhancement of retention induced by the second training. Control experiments showed that the effects were not due to alterations in motor activity or footshock sensitivity. The results suggest that NMDA receptors in the basolateral amygdala are involved in both formation of memory for inhibitory avoidance and enhancement of retention in rats given previous training.

2-Amino-5-phosphonovalerate↗

Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain.

Inflammation with expression of interleukin 6 (IL-6) in the brain occurs in many neurodegenerative disorders. To better understand the role of IL-6 in such disorders, we examined performance in a learning task in conjunction with molecular and cellular neuropathology in transgenic mice that express IL-6 chronically from astrocytes in the brain. Transgenic mice exhibited dose- and age-related deficits in avoidance learning that closely corresponded with specific progressive neuropathological changes. These results establish a link between the central nervous system expression of IL-6, inflammatory neurodegeneration, and a learning impairment in transgenic mice. They suggest a critical role for a proinflammatory cytokine in the cognitive deficits and associated neuroinflammatory changes that have been documented in neurodegenerative diseases such as Alzheimer disease and AIDS.

Age Factors↗

Avoidance learning, behavior genetics, and aging: a critical review and comment on methodology.

Animal models of human aging problems are potentially of enormous value to gerontological research. Models of behavioral problems have not often lived up to their promise. This review examines one such model system, avoidance learning in aging rodents. This model system has become increasingly popular among behavioral gerontologists, yet it has not provided the unambiguous answers to experimental questions which investigators expected. Our effort has been to determine why the system has failed, and to provide useful suggestions for future research. At the same time we have tried to provide a comprehensive review of the relevant literature and to assess the strengths and weaknesses of studies which have been conducted in the last two decades.

Adult↗

Involvement of 5-HT1A receptors in passive avoidance learning in intact and ovariectomized female rats.

The influence of chronic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT1A receptor antagonist NAN-190 (0.1 mg/kg, i.p.) injected for 14 days alone or in combination with 17beta-estradiol (0.5 microg i.m./rat/day) was studied on passive avoidance performance (PAR) and on behavior in the open field test in adult intact and ovariectomized (OVX) female rats. Administration of 5-HT1A receptor antagonist NAN-190 alone significantly improved PAR (p<0.05) in intact females with proestrus and estrus and in OVX females. Administration of 5-HT1A receptor agonist 8-OH-DPAT alone or in combination with 17beta-estradiol significantly (p<0.05) improved PAR in OVX rats and failed to normalize PAR in intact rats with proestrus and estrus. Results of the work specify the involvement of 5-HT1A receptors in the mechanisms of passive avoidance learning in OVX female rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Passive avoidance learning in the day-old chick is modulated by GABAergic agents.

Injection of drugs directly into the intermediate medial hyperstriatum ventrale (IMHV) of day-old chicks, prior to training on a chrome bead dipped in either the strong aversant methyl anthranilate (MeA), or the weak aversant quinine, allows investigation of the effects of potential amnestic and memory-enhancing agents on retention of a passive avoidance task. Chicks were injected into the left and right IMHV, with either saline or muscimol (GABA agonist), 30 minutes before training on an MeA-coated bead. On test, either 10 min, 30 min or 24 h after training, birds were presented with a dry chrome bead. Normally, trained birds will avoid the test bead; however, significantly more muscimol-injected birds pecked the dry bead than did saline-injected chicks, indicating amnesia in the muscimol-injected birds. In chicks injected bilaterally into the IMHV with bicuculline, a GABAA antagonist, 30 minutes prior to training on a quinine-coated bead, avoidance scores were significantly improved on testing at 24 h compared with saline-injected control chicks, indicating enhanced retention in bicuculline-treated birds. These results suggest a role for the GABAergic system in the acquisition and retention of passive avoidance learning in the day-old chick.

Animals↗

Impairment of passive avoidance learning following repeated administrations of antibodies against nerve growth factor in neonatal mice.

CD-1 Swiss mice were used to study the effects of repeated intracerebroventricular (i.c.v.) injections, on postnatal days (PND) 3, 6, 9, of rabbit antiserum (50 micrograms) raised against murine nerve growth factor (NGF) both on locomotor activity in an open field test (PND 10) and on a passive avoidance learning test (PND 11 and 12). While no difference was evident in locomotor activity levels between anti-NGF and control pups, an impairment of anti-NGF pups was detectable in the passive avoidance performance. Removal of endogenous NGF seems to produce a detrimental effect on a behavioural performance which is known to be under central cholinergic control, confirming previous reports on the role of NGF in early neurobehavioural responding in altricial rodents.

Acetylcholine↗

Effects of adenosine receptor agonists and antagonists on acquisition of passive avoidance learning.

A series of experiments examined the effect of the adenosine receptor agonists N(6)-cyclohexyladenosine (CHA), N(6)-phenylisopropyladenosine (R-PIA) and 5'-N-ethylcarboxamidoadenosine (NECA); the adenosine receptor antagonists theophylline, caffeine and 8-phenyltheophylline (8-PT), and the adenosine uptake inhibitor dipyridamole on acquisition of a single trial passive avoidance learning by mice. The adenosine receptor agonists CHA (0.05, 0.1, 0.2 and 0.4 mg/kg) and R-PIA (0.00625, 0.125, 0.25 and 0.5 mg/kg) administered 1 h before the training session decreased retention dose dependently while the other adenosine receptor agonist NECA (0.0025, 0.005 and 0.01 mg/kg) had no effect. The response induced by the adenosine receptor agonists CHA and R-PIA was attenuated by the pretreatment of animals with low doses of the adenosine receptor antagonists 8-PT (2.0 mg/kg) and theophylline (25 mg/kg) but not with higher doses of the antagonists. The higher doses of the antagonists decreased the passive avoidance. Dipyridamole (7.5, 15, 30, 60 and 120 mg/kg) showed no significant effect. It is concluded that adenosine A1 receptor activation decreases the acquisition of a passive avoidance response.

Adenosine↗

Autoimmunity and avoidance learning in NXRF recombinant inbred strains.

Four recombinant inbred (RI) strains, generated from NZB and RF progenitors, were tested on a two-way shuttlebox and their sera were assayed for serological factors. The four RI strains differed with respect to number of null responses and escape time. The strain with the poorest performance displayed the greatest degree of autoimmunity. The avoidance measures were correlated against the autoimmune serological parameters for the four RI strains and the two progenitors. The number of avoidances was negatively correlated with anti-DNA antibody titer, while the number of null responses showed a positive association with immune complex level. Escape time had positive correlations with IgG, IgM-RF, and immune complexes. These findings are consistent with, and extend, our prior reports that avoidance learning is inversely related to the degree of autoimmunity.

Animals↗